The overall aim of this project is to improve our understanding of the role of cell adhesion receptors and[unreadable] extracellular matrix (ECM) proteins in cardiovascular development, maintenance, repair and pathology, using[unreadable] mouse models and cell biological approaches, as well as increasing use of genome-scale approaches. Our[unreadable] main interests are in heart development, angiogenesis (both physiological and pathological) and[unreadable] hemostasis/thrombosis. All these involve cell adhesion events and our aim is to provide a deeper[unreadable] understanding of the molecular and cellular mechanisms involved. Such an understanding has major[unreadable] implications for therapeutic approaches, since cell adhesion proteins are accessible outside cells and excellent[unreadable] precedents exist for drugs that target known adhesion receptors, especially in thrombosis, inflammation and[unreadable] autoimmune disease. We have had long-standing collaborations on the roles of adhesion proteins in[unreadable] inflammation and hemostasis/thrombosis with Dr. Wagner, who is now a member of this Program Project. We[unreadable] are also collaborating with Dr. Krieger, probing the contributions of adhesion of vascular cells to the models of[unreadable] coronary heart disease that he has developed. Both of those collaborations will continue in the next grant[unreadable] period and will also incorporate collaborations on angiogenesis, a topic which has been a major component of[unreadable] our own research effort during the past funding period. In the next period, our collaborations will continue, with[unreadable] an increased focus on connections to human disease. We have many interests in common with the Lodish[unreadable] lab. and are planning additional collaborations during the next funding period investigating links among[unreadable] adiponectins, fibronectins and integrins.[unreadable] Our main aims will be as follows:-[unreadable] 1. to identify a modifier gene(s) (QTL) that we have mapped to a 5Mbp region on chromosome 4, which[unreadable] interacts with the fibronectin gene during cardiac development. Identification will be by continued SNP[unreadable] mapping combined with the mouse HapMap, cross-correlated with expression profiling data and tested by[unreadable] RNA interference.[unreadable] 2. to analyze existing strains (plus additional ones that we are generating) that are altered in their[unreadable] expression and splicing of fibronectin. Those mice will be investigated first for defects in vascular[unreadable] development and angiogenesis.[unreadable] 3. that will be complemented by in vitro analyses using FN-null endothelial cells and recombinant FN[unreadable] isoforms to test at the cell biological level their effects on the cells.[unreadable] 4. we will continue to investigate in depth the roles of various integrins in angiogenesis, with particular[unreadable] focus on integrins that act as FN receptors in the vasculature.[unreadable] 5. we will investigate contributions of FN and its splice isoforms to hemostasis and thrombosis using in[unreadable] vivo, ex vivo and in vitro approaches continuing our longstanding interest in this question and our recent[unreadable] collaborations on this topic with Dr. Wagner.[unreadable] 6. we have initiated and will expand a collaboration with Dr. Krieger to combine our expertise on adhesion[unreadable] and our mouse strains altered in many relevant adhesion receptors and ECM proteins with Dr. Krieger's[unreadable] expertise in coronary heart disease (CHD) and his mouse models of CHD.[unreadable]